Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. ...The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen-coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 × 10(9)) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach.
Multiple sclerosis (MS) is an inflammatory and demyelinating disease which leads to impairment in several functional systems including cognition. Alteration of brain networks is linked to disability ...and its progression. However, results are mostly cross‐sectional and yet contradictory as putative adaptive and maladaptive mechanisms were found. Here, we aimed to explore longitudinal reorganization of brain networks over 2‐years by combining diffusion tensor imaging (DTI), resting‐state functional MRI (fMRI), magnetoencephalography (MEG), and a comprehensive neuropsychological‐battery. In 37 relapsing‐remitting MS (RRMS) and 39 healthy‐controls, cognition remained stable over‐time. We reconstructed network models based on the three modalities and analyzed connectivity in relation to the hierarchical topology and functional subnetworks. Network models were compared across modalities and in their association with cognition using linear‐mixed‐effect‐regression models. Loss of hub connectivity and global reduction was observed on a structural level over‐years (p < .010), which was similar for functional MEG‐networks but not for fMRI‐networks. Structural hub connectivity increased in controls (p = .044), suggesting a physiological mechanism of healthy aging. Despite a general loss in structural connectivity in RRMS, hub connectivity was preserved (p = .002) over‐time in default‐mode‐network (DMN). MEG‐networks were similar to DTI and weakly correlated with fMRI in MS (p < .050). Lower structural (β between .23–.33) and both lower (β between .40–.59) and higher functional connectivity (β = −.54) in DMN was associated with poorer performance in attention and memory in RRMS (p < .001). MEG‐networks involved no association with cognition. Here, cognitive stability despite ongoing neurodegeneration might indicate a resilience mechanism of DMN hubs mimicking a physiological reorganization observed in healthy aging.
In this study, we propose that the resilience of structural hub disruption compensated by functional connectivity in the DMN underlies the stable disability compensating by the aging of RRMS.
Objective
To investigate accumulation of disability in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein‐antibody‐associated disease (MOGAD) in a changing ...treatment landscape. We aimed to identify risk factors for the development of disability milestones in relation to disease duration, number of attacks, and age.
Methods
We analyzed data from individuals with NMOSD and MOGAD from the German Neuromyelitis Optica Study Group registry. Applying survival analyses, we estimated risk factors and computed time to disability milestones as defined by the Expanded Disability Status Score (EDSS).
Results
We included 483 patients: 298 AQP4‐IgG+ NMOSD, 52 AQP4‐IgG−/MOG‐IgG− NMOSD patients, and 133 patients with MOGAD. Despite comparable annualized attack rates, disability milestones occurred earlier and after less attacks in NMOSD patients than MOGAD patients (median time to EDSS 3: AQP4‐IgG+ NMOSD 7.7 (95% CI 6.6–9.6) years, AQP4‐IgG−/MOG‐IgG− NMOSD 8.7) years, MOGAD 14.1 (95% CI 10.4–27.6) years; EDSS 4: 11.9 (95% CI 9.7–14.7), 11.6 (95% lower CI 7.6) and 20.4 (95% lower CI 14.1) years; EDSS 6: 20.1 (95% CI 16.5–32.1), 20.7 (95% lower CI 11.6), and 37.3 (95% lower CI 29.4) years; and EDSS 7: 34.2 (95% lower CI 31.1) for AQP4‐IgG+ NMOSD). Higher age at onset increased the risk for all disability milestones, while risk of disability decreased over time.
Interpretation
AQP4‐IgG+ NMOSD, AQP4‐IgG−/MOG‐IgG− NMOSD, and MOGAD patients show distinctive relapse‐associated disability progression, with MOGAD having a less severe disease course. Investigator‐initiated research has led to increasing awareness and improved treatment strategies appearing to ameliorate disease outcomes for NMOSD and MOGAD. ANN NEUROL 2024;95:720–732
Background and purpose
Extent and dynamic of neurodegeneration in progressive multiple sclerosis (MS) might be reflected by global and regional brain perfusion, an outcome at the intercept between ...structure and function. Here, we provide a first insight into the evolution of brain perfusion and its association with disability in primary progressive MS (PPMS) over several years.
Methods
Seventy‐seven persons with PPMS were followed over up to 5 years. Visits included a 3‐T magnetic resonance imaging with pulsed arterial spin labelling perfusion, the Timed 25‐Foot Walk, 9‐Hole Peg Test (NHPT), Symbol Digit Modalities Test (SDMT), and Expanded Disability Status Scale (EDSS). We extracted regional cerebral blood flow surrogates and compared them to 11 controls. Analyses focused on cortical and deep grey matter, the change over time, and associations with disability on the regional and global levels.
Results
Baseline brain perfusion of patients and controls was comparable for the cortex (p = 0.716) and deep grey matter (p = 0.095). EDSS disability increased mildly (p = 0.023), whereas brain perfusion decreased during follow‐up (p < 0.001) and with disease duration (p = 0.009). Lower global perfusion correlated with higher disability as indicated by EDSS, NHPT, and Timed 25‐Foot Walk (p < 0.001). The motor task NHPT showed associations with 20 grey matter regions. In contrast, better SDMT performance correlated with lower perfusion (p < 0.001) in seven predominantly frontal regions, indicating a functional maladaptation.
Conclusions
Decreasing perfusion indicates a putative association with MS disease mechanisms such as neurodegeneration, reduced metabolism, and loss of resilience. A low alteration rate limits its use in clinical practice, but regional association patterns might provide a snapshot of adaptive and maladaptive functional reorganization.
Neurodegeneration in progressive multiple sclerosis might be reflected by altered brain perfusion, an outcome at the intercept between structure and function. In 77 patients, we observed a decrease of arterial spin labelling (ASL) brain perfusion in a longitudinal setting. Regional association patterns indicate that ASL perfusion might provide a snapshot of adaptive and maladaptive functional reorganization.
Background:
Multiple sclerosis (MS) is characterised by accelerated brain atrophy, which relates to disease progression. Previous research shows that progressive resistance training (PRT) can ...counteract brain atrophy in other populations.
Objective:
To evaluate the effects of PRT by magnetic resonance imaging (MRI) and clinical measures of disease progression in people with MS.
Methods:
This study was a 24-week randomised controlled cross-over trial, including a Training (n = 18, 24 weeks of PRT followed by self-guided physical activity) and Waitlist group (n = 17, 24 weeks of habitual lifestyle followed by PRT). Assessments included disability measures and MRI (lesion load, global brain volume, percentage brain volume change (PBVC) and cortical thickness).
Results:
While the MS Functional Composite score improved, Expanded Disability Status Scale, lesion load and global brain volumes did not differ between groups. PBVC tended to differ between groups and higher absolute cortical thickness values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes were confirmed and reproduced when comparing relative cortical thickness changes between groups for four areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior temporal sulcus.
Conclusion:
PRT seem to induce an increase in cortical thickness, indicating that PRT have a neuroprotective or even neuroregenerative effect in relapsing-remitting MS.
Objectives
People with multiple sclerosis (pwMS) often have magnetic resonance imaging (MRI) examinations. While MRI can help guide MS management, it may be a source of anxiety for pwMS. We aimed to ...develop and validate a questionnaire on the “EMotions and Attitudes towards MRI” (MRI‐EMA).
Material and Methods
The questionnaire was developed, tested in two samples of pwMS and validated in a sample of n = 457 pwMS using exploratory (EFA) and confirmatory factor analysis (CFA).
Results
EFA revealed four factors underlying the questionnaire: fear of MRI scan, fear of MRI results, feeling of control over the disease and feeling of competence in the patient‐physician encounter. CFA confirmed the model fit. Receiving the MRI results, but not undergoing the procedure was associated with anxiety. Seeing MRI results gave participants a feeling of control over the disease. Only 50% felt competent to discuss MRI findings with their physician. Fear of MRI results was especially high and feeling of competence low in participants with a short disease duration and little MRI experience.
Conclusion
PwMS do not feel competent when discussing the role, MRI plays in their care. Receiving MRI results caused anxiety and provides some pwMS with a—perhaps false—feeling of control over the disease. The MRI‐EMA constitutes a new tool for the assessments of pwMS' feelings towards MRI, that can be applied in future research and clinical settings.
To analyse predictors for relapses and number of attacks under different immunotherapies in patients with neuromyelitis optica spectrum disorder (NMOSD).
This is a retrospective cohort study ...conducted in neurology departments at 21 regional and university hospitals in Germany. Eligible participants were patients with aquaporin-4-antibody-positive or aquaporin-4-antibody-negative NMOSD. Main outcome measures were HRs from Cox proportional hazard regression models adjusted for centre effects, important prognostic factors and repeated treatment episodes.
265 treatment episodes with a mean duration of 442 days (total of 321 treatment years) in 144 patients (mean age at first attack: 40.9 years, 82.6% female, 86.1% aquaporin-4-antibody-positive) were analysed. 191 attacks occurred during any of the treatments (annual relapse rate=0.60). The most common treatments were rituximab (n=77, 111 patient-years), azathioprine (n=52, 68 patient-years), interferon-β (n=32, 61 patient-years), mitoxantrone (n=34, 32.1 patient-years) and glatiramer acetate (n=17, 10 patient-years). Azathioprine (HR=0.4, 95% CI 0.3 to 0.7, p=0.001) and rituximab (HR=0.6, 95% CI 0.4 to 1.0, p=0.034) reduced the attack risk compared with interferon-β, whereas mitoxantrone and glatiramer acetate did not. Patients who were aquaporin-4-antibody-positive had a higher risk of attacks (HR=2.5, 95% CI 1.3 to 5.1, p=0.009). Every decade of age was associated with a lower risk for attacks (HR=0.8, 95% CI 0.7 to 1.0, p=0.039). A previous attack under the same treatment tended to be predictive for further attacks (HR=1.5, 95% CI 1.0 to 2.4, p=0.065).
Age, antibody status and possibly previous attacks predict further attacks in patients treated for NMOSD. Azathioprine and rituximab are superior to interferon-β.
Although multiple sclerosis (MS) is frequently accompanied by visuo‐cognitive impairment, especially functional brain mechanisms underlying this impairment are still not well understood. ...Consequently, we used a functional MRI (fMRI) backward masking task to study visual information processing stratifying unconscious and conscious in MS. Specifically, 30 persons with MS (pwMS) and 34 healthy controls (HC) were shown target stimuli followed by a mask presented 8–150 ms later and had to compare the target to a reference stimulus. Retinal integrity (via optical coherence tomography), optic tract integrity (visual evoked potential; VEP) and whole brain structural connectivity (probabilistic tractography) were assessed as complementary structural brain integrity markers. On a psychophysical level, pwMS reached conscious access later than HC (50 vs. 16 ms, p < .001). The delay increased with disease duration (p < .001, β = .37) and disability (p < .001, β = .24), but did not correlate with conscious information processing speed (Symbol digit modality test, β = .07, p = .817). No association was found for VEP and retinal integrity markers. Moreover, pwMS were characterized by decreased brain activation during unconscious processing compared with HC. No group differences were found during conscious processing. Finally, a complementary structural brain integrity analysis showed that a reduced fractional anisotropy in corpus callosum and an impaired connection between right insula and primary visual areas was related to delayed conscious access in pwMS. Our study revealed slowed conscious access to visual stimulus material in MS and a complex pattern of functional and structural alterations coupled to unconscious processing of/delayed conscious access to visual stimulus material in MS.
Although multiple sclerosis (MS) is frequently accompanied by visuo‐cognitive impairment, especially functional brain mechanisms underlying this impairment are still not well understood. Consequently, we used a functional MRI (fMRI) backward masking task to study visual information processing stratifying unconscious and conscious in MS. Our study revealed slowed conscious access to visual stimulus material in MS and a complex pattern of functional and structural alterations coupled to unconscious processing of/delayed conscious access to visual stimulus material in MS.
Background:
As exercise exerts neurobiological and immunomodulatory effects, it might also act as a disease-modifying intervention in MS. However, a clear mechanistic link between exercise and ...disease-modifying effects in MS has yet to be established.
Objective:
Establish recommendations for future mechanistic exercise studies in MS.
Methods:
In regular meetings, members of the mechanisms of action group within the MoXFo (Moving eXercise research Forward in MS) initiative evaluated gaps of knowledge and discussed unmet needs in mechanistic MS research.
Results:
We concluded that biomarkers assessed in translational studies in humans and animals are essential to decipher the underlying mechanisms of exercise in MS. Consequently, we defined clear definitions of different types of biomarkers examined in MS exercise studies and operationalized their use to align with the research question and optimal testing time points. Furthermore, we provide key considerations to improve the rigor of translational studies and defined minimal reporting criteria for animal studies.
Conclusion:
The resulting recommendations are intended to improve the quality of future mechanistic exercise studies in MS and consequently lead to a better understanding of therapeutic approaches.
Magnetic resonance imaging (MRI) is the key prognostic tool in people with a clinically isolated syndrome (CIS). There is increasing interest in treating people following a CIS in the hope that ...conversion to multiple sclerosis (MS) will be prevented and future disability reduced. So far, the prognostic value of MRI for disability following a CIS has not been evaluated systematically. We systematically searched MEDLINE and EMBASE. Cohort studies were selected if they reported associations of MRI and disability following a CIS, included at least 50 people with a CIS at baseline, had at least 5 years of follow‐up and obtained at least one structural MRI measurement (T1 lesions, T2 lesions, T1 contrast‐enhancing lesions or brain atrophy). We assessed the studies for quality and rated the completeness of MRI reporting. In total, 13 studies were identified reporting on the following: T2 lesion number and volume, T2 infratentorial lesion number and volume, T1 contrast‐enhancing lesions and grey matter fraction. T2 brain lesion number determined soon after the occurrence of a CIS was associated with disability progression after 5‐7 years, with an increased risk when 10 or more lesions were present. Infratentorial lesions were also associated with a higher risk of subsequent disability. The number and distribution of MRI‐visible lesions soon after a CIS are associated with disability later on, and may offer additional useful information when making treatment decisions in people with early MS. Further work is required to determine whether other measures have a higher predictive potential.
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